Anticancer activity of a novel small molecule tubulin inhibitor STK899704
We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depoly...
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| Veröffentlicht in: | PloS one 2017-03, Vol.12 (3), p.e0173311 |
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| creator | Sakchaisri, Krisada Kim, Sun-Ok Hwang, Joonsung Soung, Nak Kyun Lee, Kyung Ho Choi, Tae Woong Lee, Yongjun Park, Chan-Mi Thimmegowda, Naraganahalli R Lee, Phil Young Shwetha, Bettaswamigowda Srinivasrao, Ganipisetti Pham, Thi Thu Huong Jang, Jae-Hyuk Yum, Hye-Won Surh, Young-Joon Lee, Kyung S Park, Hwangseo Kim, Seung Jun Kwon, Yong Tae Ahn, Jong Seog Kim, Bo Yeon |
| description | We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies. |
| doi_str_mv | 10.1371/journal.pone.0173311 |
| format | Article |
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STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0173311</identifier><identifier>PMID: 28296906</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>5-Fluorouracil ; Animals ; Anticancer properties ; Antineoplastic agents ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antineoplastic drugs ; Antitumor activity ; Antitumor agents ; Apoptosis ; Benzofurans - chemistry ; Benzofurans - pharmacology ; Binding sites ; Biology and Life Sciences ; Biotechnology ; Cancer ; Cancer cells ; Cancer therapies ; Cancer treatment ; Carcinogenesis ; Carcinogens ; cdc25 Phosphatases - metabolism ; Cell cycle ; Cell Cycle Proteins - metabolism ; Cell division ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Colchicine ; Cyclin B1 ; Cyclin B1 - metabolism ; Depolymerization ; Dosage and administration ; Doxorubicin ; Drugs ; Gene expression ; Humans ; Inhibitors ; Kinases ; Laboratories ; Medical research ; Medicine and Health Sciences ; Metabolism ; Mice ; Multidrug resistance ; Neurotoxicity ; Paclitaxel ; Pharmacy ; Phosphorylation ; Physical Sciences ; Polo-like kinase ; Polo-Like Kinase 1 ; Polymerization ; Polymerization - drug effects ; Protein Serine-Threonine Kinases - metabolism ; Proteins ; Proto-Oncogene Proteins - metabolism ; Research and analysis methods ; Skin ; Skin cancer ; Spindle Apparatus - drug effects ; Taxol ; Tubulin ; Tubulin - metabolism ; Tubulin Modulators - chemistry ; Tubulin Modulators - pharmacology ; Tumor cell lines ; Tumors</subject><ispartof>PloS one, 2017-03, Vol.12 (3), p.e0173311</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-639d55c21cc3cff66e176307f050ed7c6e3150e66de74ef17eedc12da862b4883</citedby><cites>FETCH-LOGICAL-c725t-639d55c21cc3cff66e176307f050ed7c6e3150e66de74ef17eedc12da862b4883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351965/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351965/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23870,27928,27929,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28296906$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lebedeva, Irina V</contributor><creatorcontrib>Sakchaisri, Krisada</creatorcontrib><creatorcontrib>Kim, Sun-Ok</creatorcontrib><creatorcontrib>Hwang, Joonsung</creatorcontrib><creatorcontrib>Soung, Nak Kyun</creatorcontrib><creatorcontrib>Lee, Kyung Ho</creatorcontrib><creatorcontrib>Choi, Tae Woong</creatorcontrib><creatorcontrib>Lee, Yongjun</creatorcontrib><creatorcontrib>Park, Chan-Mi</creatorcontrib><creatorcontrib>Thimmegowda, Naraganahalli R</creatorcontrib><creatorcontrib>Lee, Phil Young</creatorcontrib><creatorcontrib>Shwetha, Bettaswamigowda</creatorcontrib><creatorcontrib>Srinivasrao, Ganipisetti</creatorcontrib><creatorcontrib>Pham, Thi Thu Huong</creatorcontrib><creatorcontrib>Jang, Jae-Hyuk</creatorcontrib><creatorcontrib>Yum, Hye-Won</creatorcontrib><creatorcontrib>Surh, Young-Joon</creatorcontrib><creatorcontrib>Lee, Kyung S</creatorcontrib><creatorcontrib>Park, Hwangseo</creatorcontrib><creatorcontrib>Kim, Seung Jun</creatorcontrib><creatorcontrib>Kwon, Yong Tae</creatorcontrib><creatorcontrib>Ahn, Jong Seog</creatorcontrib><creatorcontrib>Kim, Bo Yeon</creatorcontrib><title>Anticancer activity of a novel small molecule tubulin inhibitor STK899704</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.</description><subject>5-Fluorouracil</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic drugs</subject><subject>Antitumor activity</subject><subject>Antitumor agents</subject><subject>Apoptosis</subject><subject>Benzofurans - chemistry</subject><subject>Benzofurans - pharmacology</subject><subject>Binding sites</subject><subject>Biology and Life Sciences</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>cdc25 Phosphatases - metabolism</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell division</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Colchicine</subject><subject>Cyclin B1</subject><subject>Cyclin B1 - metabolism</subject><subject>Depolymerization</subject><subject>Dosage and administration</subject><subject>Doxorubicin</subject><subject>Drugs</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Multidrug resistance</subject><subject>Neurotoxicity</subject><subject>Paclitaxel</subject><subject>Pharmacy</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Polo-like kinase</subject><subject>Polo-Like Kinase 1</subject><subject>Polymerization</subject><subject>Polymerization - drug effects</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Research and analysis methods</subject><subject>Skin</subject><subject>Skin cancer</subject><subject>Spindle Apparatus - drug effects</subject><subject>Taxol</subject><subject>Tubulin</subject><subject>Tubulin - metabolism</subject><subject>Tubulin Modulators - chemistry</subject><subject>Tubulin Modulators - pharmacology</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1v0zAUhiMEYmPwDxBEQkLsoiW244_cIFUTsIpJk9jg1nKck9aVY5fYqdi_x6XZ1KBdIF_Ysp_zng-_WfYaFXNEOPq48UPvlJ1vvYN5gTghCD3JTlFF8Izhgjw9Op9kL0LYFAUlgrHn2QkWuGJVwU6z5cJFo5XT0OdKR7Mz8S73ba5y53dg89Apa_POW9CDhTwO9WCNy41bm9pE3-c3t99EVfGifJk9a5UN8Grcz7IfXz7fXlzOrq6_Li8WVzPNMY0zRqqGUo2R1kS3LWOAOCMFbwtaQMM1A4LSibEGeAkt4gCNRrhRguG6FIKcZW8PulvrgxynECQSnPMKEYYSsTwQjVcbue1Np_o76ZWRfy98v5KqT11bkJRoCg2pa6x52Za1oBWuUzUCM1KnaSWtT2O2oe5SJeBir-xEdPrizFqu_C4pU1QxmgQ-jAK9_zVAiLIzQYO1yoEf9nULxGlFSpLQd_-gj3c3UiuVGjCu9Smv3ovKRSkowwQJlqj5I1RaDXRGJ8u0Jt1PAs4nAYmJ8Duu1BCCXN58_3_2-ueUfX_ErkHZuA7eDtF4F6ZgeQB170PooX0YMirk3vH305B7x8vR8SnszfEHPQTdW5z8AZOD-UE</recordid><startdate>20170315</startdate><enddate>20170315</enddate><creator>Sakchaisri, 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activity of a novel small molecule tubulin inhibitor STK899704</title><author>Sakchaisri, Krisada ; Kim, Sun-Ok ; Hwang, Joonsung ; Soung, Nak Kyun ; Lee, Kyung Ho ; Choi, Tae Woong ; Lee, Yongjun ; Park, Chan-Mi ; Thimmegowda, Naraganahalli R ; Lee, Phil Young ; Shwetha, Bettaswamigowda ; Srinivasrao, Ganipisetti ; Pham, Thi Thu Huong ; Jang, Jae-Hyuk ; Yum, Hye-Won ; Surh, Young-Joon ; Lee, Kyung S ; Park, Hwangseo ; Kim, Seung Jun ; Kwon, Yong Tae ; Ahn, Jong Seog ; Kim, Bo Yeon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c725t-639d55c21cc3cff66e176307f050ed7c6e3150e66de74ef17eedc12da862b4883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>5-Fluorouracil</topic><topic>Animals</topic><topic>Anticancer properties</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic drugs</topic><topic>Antitumor activity</topic><topic>Antitumor agents</topic><topic>Apoptosis</topic><topic>Benzofurans - chemistry</topic><topic>Benzofurans - pharmacology</topic><topic>Binding sites</topic><topic>Biology and Life Sciences</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Cancer therapies</topic><topic>Cancer treatment</topic><topic>Carcinogenesis</topic><topic>Carcinogens</topic><topic>cdc25 Phosphatases - metabolism</topic><topic>Cell cycle</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell division</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Colchicine</topic><topic>Cyclin B1</topic><topic>Cyclin B1 - metabolism</topic><topic>Depolymerization</topic><topic>Dosage and administration</topic><topic>Doxorubicin</topic><topic>Drugs</topic><topic>Gene 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Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sakchaisri, Krisada</au><au>Kim, Sun-Ok</au><au>Hwang, Joonsung</au><au>Soung, Nak Kyun</au><au>Lee, Kyung Ho</au><au>Choi, Tae Woong</au><au>Lee, Yongjun</au><au>Park, Chan-Mi</au><au>Thimmegowda, Naraganahalli R</au><au>Lee, Phil Young</au><au>Shwetha, Bettaswamigowda</au><au>Srinivasrao, Ganipisetti</au><au>Pham, Thi Thu Huong</au><au>Jang, Jae-Hyuk</au><au>Yum, Hye-Won</au><au>Surh, Young-Joon</au><au>Lee, Kyung S</au><au>Park, Hwangseo</au><au>Kim, Seung Jun</au><au>Kwon, Yong Tae</au><au>Ahn, Jong Seog</au><au>Kim, Bo Yeon</au><au>Lebedeva, Irina V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anticancer activity of a novel small molecule tubulin inhibitor STK899704</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-03-15</date><risdate>2017</risdate><volume>12</volume><issue>3</issue><spage>e0173311</spage><pages>e0173311-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28296906</pmid><doi>10.1371/journal.pone.0173311</doi><tpages>e0173311</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-03, Vol.12 (3), p.e0173311 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1877791361 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 5-Fluorouracil Animals Anticancer properties Antineoplastic agents Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic drugs Antitumor activity Antitumor agents Apoptosis Benzofurans - chemistry Benzofurans - pharmacology Binding sites Biology and Life Sciences Biotechnology Cancer Cancer cells Cancer therapies Cancer treatment Carcinogenesis Carcinogens cdc25 Phosphatases - metabolism Cell cycle Cell Cycle Proteins - metabolism Cell division Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Colchicine Cyclin B1 Cyclin B1 - metabolism Depolymerization Dosage and administration Doxorubicin Drugs Gene expression Humans Inhibitors Kinases Laboratories Medical research Medicine and Health Sciences Metabolism Mice Multidrug resistance Neurotoxicity Paclitaxel Pharmacy Phosphorylation Physical Sciences Polo-like kinase Polo-Like Kinase 1 Polymerization Polymerization - drug effects Protein Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins - metabolism Research and analysis methods Skin Skin cancer Spindle Apparatus - drug effects Taxol Tubulin Tubulin - metabolism Tubulin Modulators - chemistry Tubulin Modulators - pharmacology Tumor cell lines Tumors |
| title | Anticancer activity of a novel small molecule tubulin inhibitor STK899704 |
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